Genome-Wide Analysis of Esophageal Adenocarcinoma Yields Specific Copy Number Aberrations that Correlate with Prognosis
Genome-Wide Analysis of Esophageal Adenocarcinoma Yields Specific Copy Number Aberrations that Correlate with Prognosis
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DOI：
10.1002/gcc.22143
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发表时间：
2014-04-01
影响因子：
3.7
通讯作者：
Barbour, Andrew
中科院分区：
文献类型：
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作者：
Frankel, Adam;Armour, Nicola;Barbour, Andrew
在过去的30年里，西方（高加索）人群中食管腺癌（EAC）的发病率迅速上升。根治性治疗以食管切除术为基础，这对生活质量有重大影响。对于那些适合治疗的患者，5年生存率约为30%。因此，需要更准确的预后工具，拷贝数畸变（CNAs）可能在这方面提供了作为前瞻性生物标志物的能力。我们使用单核苷酸多态性（SNP）阵列对54个EAC样本的CNAs进行了全基因组检查。我们的目的是描述CNA的频繁区域，定义驱动CNA，并确定与生存相关的CNA。频繁扩增的区域包括癌基因，如egfr、MYC、KLF12、andERBB2，而频繁缺失的区域包括肿瘤抑制基因，如cdkn2a /B、PTPRD、FHIT和smad4。癌症显著靶点的基因组识别（GISTIC）算法确定了可能包含驱动因素变化的24个增益区域和28个损失区域。我们在5个区域发现了61个基因，当按CNA类型（增加或减少）分层时，这些基因与生存率的统计学显著差异相关。对GISTIC和预后区基因的通路分析显示，它们在癌症相关网络中显著富集。最后，我们发现拷贝中性的杂合性缺失是目前化疗可靶向基因中CNA的常见机制，这可能导致适合此类治疗的病例报告不足。©2014 Wiley期刊公司
The incidence of esophageal adenocarcinoma (EAC) has been increasing rapidly for the past 3 decades in Western (Caucasian) populations. Curative treatment is based around esophagectomy, which has a major impact on quality of life. For those suitable for treatment with curative intent, 5‐year survival is ∼30%. More accurate prognostic tools are therefore needed, and copy number aberrations (CNAs) may offer the ability to act as prospective biomarkers in this regard. We performed a genome‐wide examination of CNAs in 54 samples of EAC using single‐nucleotide polymorphism (SNP) arrays. Our aims were to describe frequent regions of CNA, to define driver CNAs, and to identify CNAs that correlated with survival. Regions of frequent amplification included oncogenes such asEGFR,MYC,KLF12, andERBB2, while frequently deleted regions included tumor suppressor genes such asCDKN2A/B,PTPRD,FHIT, andSMAD4. The genomic identification of significant targets in cancer (GISTIC) algorithm identified 24 regions of gain and 28 regions of loss that were likely to contain driver changes. We discovered 61 genes in five regions that, when stratified by CNA type (gain or loss), correlated with a statistically significant difference in survival. Pathway analysis of the genes residing in both the GISTIC and prognostic regions showed they were significantly enriched for cancer‐related networks. Finally, we discovered that copy‐neutral loss of heterozygosity is a frequent mechanism of CNA in genes currently targetable by chemotherapy, potentially leading to under‐reporting of cases suitable for such treatment. © 2014 Wiley Periodicals, Inc.